US3719672A - 4-substituted methylene-7-amino-8-oxo-5-thia-1-aza-bicyclo(4,2,0 oct-2-ene-2-carboxylic acids - Google Patents

4-substituted methylene-7-amino-8-oxo-5-thia-1-aza-bicyclo(4,2,0 oct-2-ene-2-carboxylic acids Download PDF

Info

Publication number
US3719672A
US3719672A US00881639A US3719672DA US3719672A US 3719672 A US3719672 A US 3719672A US 00881639 A US00881639 A US 00881639A US 3719672D A US3719672D A US 3719672DA US 3719672 A US3719672 A US 3719672A
Authority
US
United States
Prior art keywords
amino
acid
oxo
thia
residue
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00881639A
Other languages
English (en)
Inventor
K Heusler
R Woodward
I Ernest
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Corp
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CH1849968A external-priority patent/CH537415A/de
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Application granted granted Critical
Publication of US3719672A publication Critical patent/US3719672A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5463—Compounds of the type "quasi-phosphonium", e.g. (C)a-P-(Y)b wherein a+b=4, b>=1 and Y=heteroatom, generally N or O
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/516—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of nitrogen-containing compounds to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/185—Saturated compounds containing keto groups bound to acyclic carbon atoms containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part

Definitions

  • the subject of the present invention are thiazabicyclic compounds, especially 7-amino-8-oxo-5-thia-lazabicyclo [4,2,0]oct-2-ene-2-carboxylic acid compounds of the formula wherein R represents a hydrogen atom or the organic residue of an alcohol, R represents a hydrogen atom or the acyl residue Ac of an organic carboxylic acid, and R represents a methylene residue which is monoor disubstituted by optionally substituted hydrocarbon residues, optionally substituted heterocyclic residues or optionally substituted heterocyclic-aliphatic residues, wherein heterocyclic groups possess aromatic character, or functional groups, as well as salts of such compounds having salt-forming groups.
  • the compounds of formula I possess the configuration of 7-amino-cephalosporanic acid; they may, therefore, also be designated as 7-amino-A -cephem-4-carboxylic acid compounds.
  • the group R can denote the organic residue of any alcohol, but especially an optionally substituted aliphatic or araliphatic hydrocarbon residue.
  • the group R primarily represents the acyl residue Ac of an organic carboxylic acid, for example, of a carbonic acid semi-derivative or of an optionally substituted aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid.
  • a hydrocarbon residue substituting the methylene group R is primarily an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residue; such a hydrocarbon residue can also be bivalent in nature and may, for example, represent a bivalent aliphatic hydrocarbon residue.
  • a functional substituent of the methylene group R is, for example, a free hydroxyl, as well as mercapto group, or hydroxyl, as well as mercapto group etherified, e.g., by an optionally substituted aliphatic, as well as aromatic or araliphatic hydrocarbon residue, or a hydroxyl, as well as mercapto group esterified, e.g. by an organic carboxylic acid, for example, an aliphatic, aromatic or araliphatic carboxylic acid, and furthermore an acyl residue, especially the acyl residue of an aliphatic, aromatic or araliphatic carboxylic acid
  • An aliphatic hydrocarbon residue is an alkyl, alkenyl or alkynyl residue, especially a lower alkyl or lower alkenyl, as well as a lower. alkynyl residue, which can, for example, contain up to seven, preferably up to four, carbon atoms.
  • Such residues can optionally be mono-, dior polysubstituted by functional groups, for example, by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto or optionally substituted phenylmercapto or phenyl-lower ester, wherein alkyl-mercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, as well as halogen atoms, and furthermore by nitro groups, optionally substituted amino groups, oxo groups, optionally functionally converted carboxyl, as well as sulfo groups, such as carbolower alkoxy, optionally N-substituted carbamoyl or cyano groups, and/or acyl, e.g., lower alkanoyl groups.
  • functional groups for example,
  • Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residues are, for example, monocyclic, bicyclic or polycyclic cycloalkyl or cycloalkenyl groups, as well as cycloalkylor cycloalkenyl-lower alkyl or -lower alkenyl groups, wherein cycloalkyl residues contain, for example, up to 12, such as three to eight, preferably three to six, ring carbon atoms, while a cycloalkenyl residue possesses, for example, up to 12, such as three to eight, especially five to eight, preferably five or six, ring carbon atoms as well as one to two double bonds; the aliphatic portion of cycloaliphatic-aliphatic residues can, for example, contain up to seven, preferably up to four, carbon atoms.
  • cycloaliphatic or cycloaliphatic-aliphatic residues can, if desired, be mono-, dior polysubstituted, for example, by optionally substituted aliphatic hydrocarbon residues, such as, for example, the optionally substituted lower alkyl groups mentioned above, or, for example, like the above-mentioned aliphatic hydrocarbon residues, by functional groups.
  • An aromatic hydrocarbon residue is, for example, a monocyclic or bicyclic aromatic hydrocarbon residue, especially a phenyl, as well as a biphenylyl or naphthyl residue which can optionally be mono-, dior polysubstituted, for example, like the above-mentioned aliphatic and cycloaliphatic hydrocarbon residues.
  • An araliphatic hydrocarbon reside is an optionally substituted aliphatic hydrocarbon residue possessing, for example, up to three optionally substituted, monocyclic or bicyclic aromatic hydrocarbon residues and primarily represents a phenyl-lower alkyl or phenyllower alkenyl, as well as phenyl-lower alkynyl residue, with such residues containing one to three phenyl groups and optionally being mono-, dior polysubstituted in the aromatic and/or aliphatic portion, for example, like the above-mentioned aliphatic and cycloaliphatic residues.
  • a bivalent aliphatic hydrocarbon residue is primarily a lower alkylene, as well as a lower alkenylene residue which, for example, contains up to eight, preferably four to five, carbon atoms and which can, if desired, be substituted, for example, like the above-mentioned cycloaliphatic residues.
  • the heterocyclic portion of a heterocyclic or heterocyclic-aliphatic residue is especially a monocyclic, as well as bicyclic or polycyclic azacyclic, thiacyclic, oxacyclic, thiazacyclic, oxazacyclic or diazacyclic residue of aromatic character, which can optionally be mono-, dior polysubstituted, for example, like the above-men tioned cycloaliphatic residues.
  • the aliphatic portion is heterocyclic-aliphatic residues can, for example, have the significance given for the corresponding cycloaliphatic-aliphatic or araliphatic residues.
  • the acyl residue of a carbonic acid semi-derivative is preferably the acyl residue of a corresponding half- .
  • the esterifying organic residue represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or or araliphatic hydrocarbon residue or a heterocyclicaliphatic residue, primarily the residue of an optionally substituted lower alkyl half-ester of carbonic acid (i.e., a carbo-lower alkoxy residue which is optionally substituted in the lower alkyl portion), as well as a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl halfester of carbonic acid which is optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl portion (i.e., a carbo-lower alkenyloxy, carbocycloalkoxy, carbophenyl
  • Acyl residues of a carbonic acid half-ester are, furthermore, acyl residues of lower alkyl halfesters or carbonic acid, in which the lower alkyl portion contains a heterocyclic group, for example, one of the above-mentioned heterocyclic groups of aromatic character as substituent, and wherein the lower alkyl residue and the heterocyclic group can optionally be substituted; such acyl residues are carbo-lower alkoxy groups which contain an optionally substituted heterocyclic group of aromatic character in the lower alkyl residue.
  • the acyl residue of an aliphatic carboxylic acid is, for example, the corresponding residue of an alkanecarboxylic, as well as alkenecarboxylic or alkynecarboxylic acid, primarily lower alkane carboxylic, as well as lower alkenecarboxylic or lower alkynecarboxylic acid, which is optionally substituted, for example, like the above-mentioned aliphatic hydrocarbon residues, and which can, for example, contain up to seven, especially up to four, carbon atoms.
  • the acyl residue of a cycloaliphatic or cycloaliphatic-aliphatic carboxylic acid is, for example, the acyl residue of a cycloalkanecarboxylic or cycloalkenecarboxylic acid or cycloalkylor cycloalkenyllower alkanecarboxylic or -lower alkenecarboxylic acid, which is optionally substituted, for example, like the-abovementioned cycloaliphatic or cycloaliphatic aliphatic hydrocarbon residues, and in which a cycloalkyl or cycloalkenyl residue, as well as the aliphatic portion of cycloaliphatic-aliphatic carboxylic acids can, for example, have the number of carbon atoms and/or double bonds specified above for corresponding residues and can optionally be substituted, for example, as indicated.
  • the acyl residue of 'an aromatic carboxylic acid is primarily the residue of a monocyclic or bicyclic aromatic carboxylic acid, which can optionally be substituted, for example, like the above-mentioned cycloaliphatic residue.
  • the araliphatic portion in the acyl residue of an araliphatic carboxylic acid has, for example, the abovementioned significance; an araliphatic carboxylic acid primarily denotes a phenyl-lower alkanecarboxylic or phenyl-lower alkenecarboxylic acid, in which the phenyl residue and/or the aliphatic portion can optionally be substituted, for example, like the above-mentioned cycloaliphatic or aliphatic groups.
  • the heterocyclic residue is primarily of aromatic character and is preferably a monocyclic, as well as a bicyclic or polycyclic residue.
  • lt primarily represents a monocyclic, as well as bicyclic or polycyclic azacyclic oxacyclic, thiacyclic, diazacyclic, oxazacyclic or thiazacyclic residue which is optionally substituted, for example, like the above-mentioned cycloaliphatic residue.
  • the heterocyclic residue has, for example, the above-mentioned significance, while the aliphatic portion, like, for example, in an araliphatic carboxylic acid, represents an optionally substituted lower alkyl, as well as lower alkenyl residue.
  • a hydroxyl group which is etherified by an optionally substituted aliphatic hydrocarbon residue is, for example, an alkoxy, as well as alkenyloxy or alkynyloxy group, especially a lower alkoxy, as well as lower alkenyloxy or lower alkynyloxy group, wherein the organic residues of these groups can, for example, like the above-mentioned aliphatic hydrocarbon residues, be mono-, dior max by functional groups, such as free, etherified or esterified hydroxyl or mercapto groups, nitro groups, optionally mu amino, optionally functionally converted carboxyl or acyl groups.
  • Etherified hydroxyl groups are, furthermore, .op
  • tionally substituted phenyloxy, phenyl-lower alkoxy or phenyl-lower alkenyloxy groups wherein the hydrocarbon residues of hydroxyl groups etherified in such a manner can be mono-, dior polysubstituted by hydrocarbon groups or functional groups, e.g., as specified above.
  • a lower alkyl residue is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl group
  • a lower alkenyl residue can, for example, be a vinyl, allyl, isopropenyl, 2- or 3-methyallyl or 3-butenyl group
  • a lower alkynyl residue for example, a propargyl or 2-butinyl group.
  • Optionally substituted aliphatic hydrocarbon residues especially lower alkyl groups, which can, inter alia, also substitute cycloaliphatic, cycloaliphaticaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic residues, contain, for example, the above-mentioned substituents.
  • Such substituted groups are, for example, hydroxy-lower alkyl or lower alkoxylower alkyl groups, and especially halogeno-lower alkyl groups, such as monohalogenated, dihalogenated or polyhalogenated lower alkyl groups, for example, methyl, ethyl or l-propyl or 2-propyl groups.
  • Residues of the latter type especially 2-halogen-lower alkyl residues, such as 2,2,2-trichloroethyl or 2-iodoethyl groups, primarily represent halogenated lower alkyl residues R
  • a cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohepty], as well as an adamantyl group
  • a cycloalkenyl group is, for example, a 2- or 3-cyclopentenyl, l-, 2- or 3- cyclohexenyl or 3-cycloheptenyl, as well as 2- cyclopropenyl group.
  • a cycloalkyl-lower alkyl or lower alkenyl residue is, for example, a cyclopropyl-, cyclopentyl-, cyclohexylor cycloheptyl-methyl, -l,lethyl or -l,2-ethyl, -l,l-propyl, -l,2-propyl or -l,3- propyl, -vinyl or -allyl group
  • a cycloalkenyllower alkyl or -lower alkenyl group represents, for example, a l-, 2 or 3-eyclopentenyl-, 1-, 2- or 3- cyclohexenylor I-, 2- or 3-cycloheptenyl-methyl, -l ,1- ethyl or -l,2-ethyl, -l,l-propyl, -l,2-propyl or -1,3- propyl, -vinyl or
  • a naphthyl residue is a lor Z-naphthyl residue, while a biphenylyl group is primarily a 4-biphenylyl group.
  • a phenyl-lower alkyl or phenyl-lower alkenyl residue is, for example, a benzyl, lor 2-phenylethyl, l-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, lor 2- naphthylmethyl, styryl or cinnamyl residue.
  • a lower alkylene or lower alkenylene residue is, for example, represented by 1,2-ethylene, 1,3-propylene,
  • Heterocyclic residues of aromatic character are, for example, monocyclic monoazacyclic, monothiacyclic or mono-oxacyclic residues of aromatic character, such as pyridyl, e.g., 2-, 3- or 4-pyridyl residues, thienyl, e.g., 2-thienyl residues, or fury], e.g. 2-furyl residues, or bicyclic monoazacyclic residues of aromatic character, such as quinolinyl, e.g., Z-quinolinyl or 4-quinolinyl residues, or'isoquinolinyl, e.g., l-isoquinolinyl residues,
  • heterocyclic-aliphatic residues are lower alkyl or lower alkenyl residues which contain heterocyclic residues, such as those mentioned above.
  • lower alkoxy for example, methoxy, ethoxy, n-propyloxy,- isopropyloxy, n-butyloxy, isobutyloxy, sec.-butyloxy, tert.-butyloxy, npentyloxy or tert.-pentyl-oxy groups, as well as substituted lower alkoxy groups, such as halogeno-lower alkoxy groups, especially 2-halogeno-lower alkoxy, for example, 2,2,2-trichloroethoxy or 2-iodoethoxy groups, and furthermore lower alkenyloxy, for example, vinyloxy or allyloxy groups, lower alkylenedioxy, for example, methylenedioxy or ethylenedioxy, as well as isopropylidene-dioxy groups, phenyloxy groups, or
  • phenyl-lower alkoxy for example, benzyloxy or 1- or 2- phenylethoxy groups, or lower alkoxy groups, which are substituted by monocyclic monoazacyclic, monooxacyclic or monothiacyclic groups of aromatic character, such as pyridyl-lower alkoxy, for example, 2-
  • pyridylmethoxy for example, furfuryl-oxy, or thienyl-lower alkoxy, for example 2- thenyloxy groups.
  • Etherified mercapto groups are, for example, lower alkylmercapto, e.g., methylmercapto or ethylmercapto groups, phenylmercapto groups, or phenyl-lower alkylmercapto, for example, benzylmercapto groups.
  • Esterified hydroxyl groups are primarily halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, as well as lower alkanoyloxy groups, for example, acetyloxy or propionyloxy groups.
  • Substituted amino groups are monoor di-substituted amino groups, which contain as substituents primarily optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon residues, as well as acyl groups.
  • Such amino groups are especially lower alkylamino or di-lower alkylamino, for example, methylamino, ethylamino, dimethylamino or diethylamino groups, or lower alkyleneamino groups which are optionally interrupted by hetero-atoms, such as oxygen or sulphur atoms, as well nitrogen atoms which are optionally substituted, for example, by lower alkyl groups, such as pyrrolidino, piperidino, morpholino, thiamorpholino or 4-methyl-piperazino groups, as well as acylamino, especially lower alkanoylamino, such as acetylamino or propionylamino groups.
  • a carbo-lower alkoxy residue is, for example, a carbomethoxy, carbethoxy, carbo-n-propyloxy, carboisopropyloxy, carbo-tert.-butyloxy or carbo-tert.-pentyloxy group.
  • Nsubstituted carbamoyl groups are, for example, N-lower alkylor N,N-di-lower alkyl-carbamoyl groups, such as N-methyl-, N-ethyl-, N,N- dimethylor N,N-diethyl-carbamoyl groups.
  • a carbo-lower alkenyl residue is, for example, the carbovinyloxy group, while carbo-cycloalkoxy and carbo-phenyl-lower alkoxy groups, in which the cycloalkyl or phenyl-lower alkyl residue have the above-mentioned significance, for example, represent carbo-adamantyloxy or carbo-benzyloxy, as well as carbo-diphenylmethoxy or carbo-(a-4-biphenylyl-amethyl-ethoxy) groups.
  • Carbo-lower alkoxy groups in which the lower alkyl residue is substituted by monocyclic, mono-azacyclic, monooxacyclic or monothiacyclic groups are, for example, carbo-furyl-lower alkoxy, such as carbofurfuryloxy groups, or carbo-thienyl-lower alkoxy, such as carbo-2-thenyloxy groups.
  • a lower alkanecarboxylic or lower alkenecarboxylic acid is, for example, acetic, propionic, butyric, isobutyric, valeric, pivalic or acrylic acid, while a cycloalkanecarboxylic or cycloalkenecarboxylic acid, or a cycloalkylor cycloalkenyl-lower alkanecarboxylic or lower alkenecarboxylic acid denotes, for example, a cyclopentanecarboxylic, cyclohexanecarboxylic or 3- cyclohexenecarboxylic acid, cyclopentylpropionic, cyclohexylacetic, 3-cyclohexenylacetic or hexahydrocinnamic acid.
  • a monocyclic or bicyclic aromatic carboxylic acid is, for example, benzoic acid or lor Z-naphthalenecarboxylic acid, and a phenyl-lower alkanecarboxylic or phenyl-lower alkenecarboxylic acid is, for example, phenylacetic, phenyl-propionic or cinnamic acid.
  • heterocyclic carboxylic acids nicotinic or isonicotinic acid, Z-thiophenecarboxylic, Z-furanecarboxylic, 2- or 4-quinolinecarboxylic or l-isoquinolinecarboxylic acid may be mentioned, and as corresponding lower alkanecarboxylic or lower alkenecarboxylic acids substituted by heterocyclic residues, for example, 2-, 3- or 4-pyridy1acetic, 2-thienyl-acetic, 2- furylacetic or 2-furylacrylic acid.
  • the above carboxylic acids also furnish the above mentioned acyl, particularly lower alkanoyl, e.g., acetyl or propionyl residues.
  • the compounds of formula I especially those, in which R represents a preferably easily removable organic residue of an alcohol and- R represents a hydrogen atom or an acyl residue, or in which R, stands for a hydrogen atom and R represents a hydrogen atom or an acyl residue which is preferably easily removable, for example, the easily removable acyl residue of a carbonic acid semi-derivative, especially, which can be converted to the above-mentioned pharmacologically active compounds in a manner which is in itself known.
  • the compounds of the present invention can be prepared, when a compound of the formula wherein R, has the above given meaning, being primarily one of the previously mentioned organic residues, especially one of the easily removable residues, R stands for hydrogen or an acyl residue Ac which is easily removable under acidic conditions, R denotes an organic residue and R is a hydrogen atom, when R represents an acyl group Ac, or R and R together denote a disubstituted carbon atom, when R represents a hydrogen atom or an acyl group Ac, and R, represents a methyl residue having at least one hydrogen atom and being monoor disubstituted by optionally substituted hydrocarbon residues, optionally substituted heterocyclic residues or optionally substituted heterocyclic-aliphatic residues, in which a heterocyclic group has aromatic character, or functional groups, is subjected to ring closure by treatment with an acidic reagent, and,-if desired, a compound of the formula I resulting from the procedure is converted into another compound of the Formula I and/or,
  • a methyl residue which is substituted, e.g., by optionally substituted aliphatic or aromatic hydrocarbon residues, for example, the benzhydryl, trityl, tert.-butyl or tert.-pentyl, furthermore the adamantyl residue.
  • An acyl residue Ac is primarily the acyl residue of a carbonic acid-semiester easily removable under such conditions, such as a carbo-lower alkoxy residue, which in oz-position of the lower alkyl portion is branched and/or substituted in aor B-position, e.g., by optionally substituted aromatic o'r araliphatic hydrocarbon residues, such as phenyl or 4-biphenylyl groups, or by optionally substituted heterocyclic residues of aromatic character, such as 2-furyl groups, or halogen, e.g., chlorine atoms, furthermore, a carbo-lower alkenyloxy residue or a carbo-cycloalkoxy residue optionally substituted in a-position, especially, for example, the carbo-tert.-butyloxy residue, as well as carbo-tert.-pentyloxy, carbo-vinyloxy, carbo-adamantyloxy
  • R primarily represents and easily removable aliphatic hydrocarbon residue which in the linkage position is preferably unsaturated, such as a lower alkenyl residue, especially a 2-propenyl residue,'or substituted by a hetero-residue, for example, by an etherified or esterified hydroxyl group, for example, a lower alkoxy 'or lower alkanoyloxy group or a halogen atom, such as a lower alkyl, for example, methyl, ethyl, n-propyl or isopropyl residue, as well as an appropriate cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon residue which is preferably unsaturated in the linkage position or substituted by a hetero-residue.
  • unsaturated such as a lower alkenyl residue, especially a 2-propenyl residue,'or substituted by a hetero-residue
  • a hetero-residue for example
  • the two substituents of the disubstituted carbon atom can also be taken together and represent, for example, a bivalent aliphatic hydrocarbon residue which is optionally substituted and/or interrupted by hetero-atoms.
  • the two residues R and R together represent a carbon atom which is disubstituted by two lower alkyl, especially methyl groups.
  • the above ring closure is preformed by treatment with a strong, preferably oxygen-containing, inorganic or organic acid, for example, an organic carboxylic or sulphonic acid, especially with a strong lower alkanecarboxylic acid, which is optionally substituted by hetero atoms or residues and is preferably halogeno-substituted, such as an a-halogenoacetic acid or u-halogenopropionic acid, in which halogen preferably denotes fluorine, as well as chlorine, primarily trifluoroacetic acid, and also an aryl-sulphonic acid, such as p-toluenesulphonic acid, as well as mixtures of acids, e.g., p-toluene sulfonic and acetic acid.
  • a strong, preferably oxygen-containing, inorganic or organic acid for example, an organic carboxylic or sulphonic acid, especially with a strong lower alkanecarboxylic acid, which is optionally substituted
  • the process is carried out in the absence or presence of an inert solvent, for example, dioxane, or of a mixture of diluents, preferably while cooling, for example, at temperatures of about -30C to about +lC, preferably at about 25C to about 0C, if necessary, in an inertgas atmosphere, such as nitrogen atmosphere.
  • an inert solvent for example, dioxane
  • a mixture of diluents preferably while cooling, for example, at temperatures of about -30C to about +lC, preferably at about 25C to about 0C, if necessary, in an inertgas atmosphere, such as nitrogen atmosphere.
  • a resulting compound of the Formula I may be converted into another compound of the Formula I; such conversion may also take place under the acidic conditions of the ring-closure.
  • an acyl group Ac easily removable under acidic conditions, particularly the carbo-tert.-butyloxy group, and/or an ester grouping,
  • a carbo-tert.-butyloxy group Ac and/or a carbo-tert.-butyloxy group -COOR may-be removed and/or converted into the free carboxyl group by treatment with trifluoroacetic acid.
  • a residue R such as a cyclopropylidene group, may be converted into another group R, the latter, for example, into the 3-hydroxy-1,l-propylidene group.
  • a suitably esterified carboxyl group can be liberated in a manner which is in itself known.
  • an esterified carboxyl' group which, for example, contains a polysubstituted methyl group, such as the benzhydryl, tert.-butyl, tert.-pentyl or adamantyl group can be liberated by treatment with an acid, such as trifluoroacetic acid.
  • an acid such as trifluoroacetic acid.
  • such reaction may take place simultaneously with the ring-closure performed in accordance with the invention, that is to say under acid conditions, especially in the presence of trifluoroacetic acid.
  • a carboxyl' group esterified by, for example, a 2-halogeno-lower alkyl group, such as the 2,2,2-trichloroethyl, as well as 2-iodoethyl group; can be any suitable compound obtained by, for example, a 2-halogeno-lower alkyl group, such as the 2,2,2-trichloroethyl, as well as 2-iodoethyl group;
  • nascent hydrogen such as zinc, zinc alloys, for example, zinc-copper, or zinc amalgam
  • acids which optionally contain water, or acidic reagents, such as organic carboxylic acids, for example, lower alkanecarboxylic acids, e.g.
  • acetic acid such as 90 percent aqueous acetic acid, furthermore ammonium chloride or pyridine hydrochloride, or alcohols, such as lower alkanols, optionally in the presence.
  • acids, or alkali metal amalgams for example, sodium or potassium amalgam, or aluminum amalgam, preferably in the presence of a moist solvent, such as ether or lower alkanols, furthermore by treatment with strongly reducing metal salts, such as chromium-II compounds, for example, chromium-Il-chloride or chromium-llacetate, preferably in the presence of aqueous media, containing water-miscible organic solvents, such as lower alkanols, lower alkanecarboxylic acids or ethers, for example, methanol, ethanol, acetic acid,
  • Compounds having a free carboxyl group can, in a manner which is in itself known, for example, be converted to their salts, such as alkali metal, for example, sodium or potassium salts, or alkaline earth metal, for example, calcium or magnesium salts, or ammonium salts, for example, with ammonia or amines, or can be liberated from salts, for example, by treatment with acidic reagents.
  • salts such as alkali metal, for example, sodium or potassium salts, or alkaline earth metal, for example, calcium or magnesium salts, or ammonium salts, for example, with ammonia or amines, or can be liberated from salts, for example, by treatment with acidic reagents.
  • Free carboxyl groups can be esterified according to methods which are in themselves known, for example, by treatment with a diazo compound, such as a diazolower alkane, for example, diazomethane or diazoethane, or with a phenyl-diazo-lower alkane, for example, phenyl-diazomethane or diphenyldiazomethane, or by reaction with a hydroxyl compound suitable-for esterification, such as, for example, an alcohol, in the presence of an esterifying agent, such as a carbodiimide, for example, dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or according to any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of the hydroxyl compound, especially of an alcohol and a strong inorganic acid or a strong organic sulphonic acid.
  • a diazo compound such as a diazolower alkan
  • acid halides especially acid chlorides, as well as activated esters, such as, for example, esters with N-hydroxy-nitrogen compounds, or reactive mixed anhydrides formed, e.g., with halogenoformic acid esters or trifluoroacetic acid, can be converted to esters by reaction with hydroxyl compounds, such as alcohols, optionally in the presence of a base, such as pyridine.
  • hydroxyl compounds such as alcohols
  • ln compounds having a free amino group can be acylated according to methods which are in themselves known, for example, by treatment with an acid, especially an organic carboxylic acid or a reactive acid derivative thereof, such as a halide, for example,
  • anhydride including any suitable inner anhydride of an organic carboxylic acid, i.e., a ketene, or that of a carbamic or thiocarbamic acid, i.e., an isocyanate or isothiocyanate, as well as a mixed anhydride
  • an activated ester if necessary, for example, when using the free acid as the acylating agent, suitable condensing reagents, such as carbodiimides, for example, dicyclohexylcarbodiimide,' can be employed.
  • a free amino group, formed under the conditions of the ring closure according to the invention may, if desired, be acylated without isolating the product of the process.
  • an acyl group representing the residue R may be replaced by hydrogen according to known methods, for example, by treatment with an imido halide-forming reagent, conversion of the imido halide into the corresponding imino ether and cleavage of the latter.
  • Imido halide-forming reagents are, for example, acid halides, e.g., chlorides or bromides, particularly those of phosphorus containing acids, such as phosphorus oxyhalides or phosphorus trihalides and particularly pentahalides, e.g., phosphorus oxychloride, phsophorus trichloride and above all phosphorus pentachloride.
  • acid halides e.g., chlorides or bromides
  • phosphorus containing acids such as phosphorus oxyhalides or phosphorus trihalides
  • pentahalides e.g., phosphorus oxychloride, phsophorus trichloride and above all phosphorus pentachloride.
  • the reaction with the imido halide-forming reagent is preferably carried out in the presence of a suitable, particularly organic base, primarily a tertiary amine, e.g., a tertiary aliphatic amine or diamine, such as a trilower alkyl-amine, e.g.
  • a suitable, particularly organic base primarily a tertiary amine, e.g., a tertiary aliphatic amine or diamine, such as a trilower alkyl-amine, e.g.
  • an N-substituted e.g., N- lower
  • the imido halide-forming reagent and of the base are used; however, the latter may be present in an excess or smaller amount, for example, in an about 0.2 to about 1 molar amount or alternatively in an about 10-fold, particularly a 3- to 5-fold excess.
  • reaction with imido halide-forming reagent is advantageously performed while cooling, for example, at temperatures of about +C to about 50 C; one may, however, also work at higher temperatures, for
  • the imido halide-compound which usually is processed without isolation, is converted into the imino ether by treatment with alcohols, preferably in the presence of the above bases.
  • alcohols are for example, aliphatic, as well as araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g., chlorinated, or additional hydroxy groups containing lower alkanols, e.g., ethanol, tert.-butanol or 2,2,2- trichloroethanol, and particularly methanol, as well as optionally substituted phenyl-lower alkanols, such as benzyl alcohol.
  • an excess for example, an up to l00-fold excess of the alcohol is used, and the reaction is preferably carried out while cooling, for example, at temperatures of about +10C to about -50C.
  • the imino-ether. compound is undergoing cleavage without isolation.
  • the cleavage of the imino ether to the amine compound of the Formula I, in which R stands for hydrogen, can be carried out by treatment with a suitable hydroxy compound.
  • Water is preferably used as the reagent, or a mixture of an alcohol with water, normally in an acidic medium, for example, at a pl-l-value of about 1 to about 5, which, if necessary, is obtained by the addition of a basic reagent, such as an aqueous alkali metal hydroxide, e.g., sodium or potassium hydroxide, or of an acid, e.g., a mineral acid or an organicacid, such as hydrochloric, sulfuric, phosphoric, fluoboric, trifluoroacetic or ptoluene sulfonic acid.
  • a basic reagent such as an aqueous alkali metal hydroxide, e.g., sodium or potassium hydroxide
  • An easily removable acyl group Ac is removed according to known methods, a carbo-Z-halogeno-lower alkoxy, e.g., carbo-2,2,2-tricholoroethoxy or carbo-2- iodoethoxy group, for example, by treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or a carbo-lower alkoxy group branched or substituted in oz-position of the lower alkyl portion such as carbo-tert.-butyloxy, for example, by treatment with a strong, oxygen-containing acid, e.g., trifluoro-acetic acid.
  • a chemical reducing agent such as zinc in the presence of aqueous acetic acid
  • a carbo-lower alkoxy group branched or substituted in oz-position of the lower alkyl portion such as carbo-tert.-butyloxy
  • a strong, oxygen-containing acid e.g.,
  • Resulting mixtures of isomers can be resolved into the individual isomers according to methods which are in themselves known, for example, by fractional crystallization adsorption chromatography (column or thin layer chromatography) or other processes.
  • Resulting racemates can be resolved into the antipodes in the usual manner, for example, by forming a mixture of diastereoisomeric salts with optically active salt-forming reagents, resolving the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds, or by fractional crystallization from optionally active solvents, with the more active antipode preferably being isolated.
  • the process also comprises those modifications according to which compounds formed as intermediates in the process are used as starting materials and the remaining process stages are carried out with these, or the process is interrupted at any stage; furthermore, starting materials can be used in the form of derivatives or may be formed during the reaction.
  • the hydroxyl group can by treatment with a suitable esterifying agent, for example, a halogenating agent, such as a thionyl halide, for example, thionyl chloride, a phosphorus oxyhalide, especially oxychloride, or a halo'genophosphonium halide, such as triphenylphosphine dibromide or diiodide, or a suitable organic sulphonic acid halide, such as a sulphonic acid chloride, preferably in the presence of a basic reagent, primarily an organic basic reagent, such as an aliphatic tertiary amine, for example, triethylamine or ethyldiisopropylamine, or a heterocyclic base of the pyridine type, for example, pyridine or collidine, be converted into a reactive esterified hydroxy
  • X represents the reactive esterified hydroxyl group, primarily a halogen atom, especially a chlorine or bromine atom, as well as an iodine atom, but also an organic sulphonyloxy group, primarily an aliphatic or aromatic sulphonyloxy group, for example, an optionally substituted lower alkyl-sulphonyloxy group, such as methylsulphonyloxy,ethylsulphonyloxy or 2- hydroxy-ethylsulphon'yloxy group, or an optionally substituted phenylsulphonyloxy group, for example, 4- methyl-phenylsulphonyloxy, 4-bromophenylsulphonyloxy or 3-nitrophenylsulphonyloxy group, with a phosphine compound of the formula wherein each of the groups R R and R represents an optionally substituted hydrocarbon residue, primarily an optionally substituted lower alkyl
  • the desired starting material of the Formula II is obtained.
  • a resulting mixture of isomeric compounds is separated according to known methods and the starting materials of the Formula II may be obtained in pure form.
  • an acyl group Ac may be replaced by hydrogen, for example, as described above via the imido halide and imino ether, and, if desired or necessary, hydrogen may be replaced by the easily removable acyl group Ac", for example, according to the above described acylating procedure.
  • An easily removable acyl group Ac may be removed in a per se known manner and, if desired, may be replaced by another acyl group Ac.
  • a chemical reducing agent in the presence of water, for example, with zinc in the form of the corresponding acid by heating, with the 2-propenylmercapto grouping being formed.
  • the formyl group bonded to the ring-nitrogen atoms can be removed by hydrolysis, alcoholysis, ammonolysis or aminolysis, as well as by treatment with a suitable decarbonylation agent, such as a tris-(tri-organically substituted phosphine)-rhodium halide, for example, tris-(triphenyl-phosphine)-rhodium chloride, in a suitable solvent, for example, benzene, or by conversion of the formyl group to the carbinol group, for example, by treatment with catalytically activated hydrogen in the presence of a palladium catalyst and glacial acetic acid or tetrahydrofuran, containing hydrochloric acid.
  • a suitable decarbonylation agent such as a tris-(tri-organically substituted phosphine)-rhodium halide, for example, tris-(triphenyl-phosphine)-rhodium chloride
  • a suitable solvent
  • the 2-acyloxy-2-propyl residue in a resulting compound can be replaced by a different organic residue by treatment with a weakly basic reagent, such as an alkali metal hydrogen carbonate or pyridine, in the presence of a reactive ester of an alcohol, such as a suitable halide.
  • a weakly basic reagent such as an alkali metal hydrogen carbonate or pyridine
  • the invention also comprised the starting materials of the Formula II, especially those of the formulas C OR, (Ila) and t wherein R, and R have the above-mentioned significance, R stands for hydrogen or the acyl residue Ac', Ac represents an easily, especially under acidic conditions removable carbo-lower alkoxy, especially the carbo-tert.-butyloxy group, R is a 2-propenyl or 2- lower alkanoyloxy-Z-propyl group, and each of R and R is lower alkyl, especially methyl, and R, stands for a methyl residue, which contains at least one hydrogen atom and is substituted by lower alkyl, especially methyl residues, as well as lower alkanoyl, especially acetyl or propionyl residues, and also cycloalkyl, for example, cyclopentyl or cyclohexyl residues, or by phenyl or phenyl-lower alkyl residues which optionally contain substituents, for example, those
  • the compounds of the present invention having useful pharmacological.properties can be used in the form of pharmaceutical preparations, in which they are present as a mixture together with a solid or liquid pharmaceutical excipient, and which are suitable for enteral or parenteral administration.
  • Suitable excipients which are inert towards the active substances are, for example, water, gelatine, saccharides, such as lactose, glucose or sucrose, starches, such as corn starch, wheat starch or arrowroot, stearic acids or salts thereof, such as magnesium stearate or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known excipients.
  • the preparations may be in a solid form, for example, as tablets, dragees, capsules or suppositories, or in a liquid form, for example, as solutions, suspensions or emulsions. They may be sterilized and/or contain auxiliary substances, such as preserving, stabilizing wetting, emulsifying, or solubilizing agents, salts for regulating the osmotic pressure and/or buffers. They may, furthermore, contain other pharmacologically useful substances.
  • the pharmaceutical preparations which are also encompassed by the present invention, can be manufactured in a manner which is in itself known.
  • EXAMPLE 1 A solution of 0.1211 g of isomer A of a-(2carbotert.-butyloxy-3 ,3dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo [3,2,0]heptyl)-a-(phenylacetylmethylene)- acetic acid tert.-butyl ester in 1.2 ml of pre-cooled trifluoroacetic acid is allowed to stand for 21 hours at 20C and is then diluted with 9 ml of dioxane.
  • the mixture containing the 7-amino-4-benzylidene-8-oxo- 5-thia-lazabicyclo[4,2,0]0ct-2-ene-2-car-boxylic acid (configuration of 7-amino-cephalosporanic acid) or 7- amino-2-benzyliden-A -cephem4-carboxylic acid, is mixed with a solution of 0.129 g of phenyloxy-acetyl chloride in 1 m1 of dioxane. After standing for 2% hours at room temperature, the reaction mixture is treated with 1 ml of water and is allowed to stand for a further hour.
  • EXAMPLE 2 A solution of 0.5625 g of isomer A of a-(2-carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo-[3,2,0]heptyl)-oz-(phenylacetylmethylene)- acetic acid tert.-butyl ester in 4 ml of trifluoroacetic acid, which has been precooled, is allowed to stand for 20 hours at -20C and for 1 hour at room temperature.
  • reaction mixture is allowed to stand for 3 hours at room temperature and is then mixed with 2 ml of water; the mixture is allowed to stand for 1 hour at room temperature, and then cooled to -lC, and the volatile constituents are evaporated off by lyophilization under a high vacuum. The residue is taken up in 4 ml of benzene, whereupon crystallization starts.
  • the crystalline material is filtered off after 24 hours and washed with benzene; the 4- benzylidene-7-N-phenylacetyl-amino-8oxo-5-thia-lazabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7-N phenyl-acetyl-amino-A -cephem-4 carboxylic acid of the formula 060i 7 I which after recrystallization from aqueous ethanol (90 percent) melts at 224-226C, is thus obtained; thin layer chromatogram: Rf 0.30 (silica gel; in the system toluene/acetic acid/water, :4:1); ultra-violet absorption spectrum: in ethanol, a 353 ml).
  • the mother liquor is chromatographed on 10 g of acid-washed silica gel; phenylacetic acid together with a yellow neutral material are eluted with a 100:5-mixture of benzene and acetone, and thereafter a further quantity of 4-benzylidene-7-N-phenylacetyl-amino-8- oxo-5-thial -azabi-cyclo[ 4,2,0]oct-2-ene-2-carboxylic acid is eluted with a 2:1-mixture of benzene and acetone and crystallizes after adding a little acetone, mQp. 223225C.
  • the mother liquor is chromatographed on 5 g' of acid-washed silica gel; a further quantity of the desired 7-N-acetylamino-4-benzylidene-8-oxo-5-thia-l-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid, together with a'neutral product which is enriched in the first fractions, is eluted with a 4:1-mixture of benzene and acetone.
  • EXAMPLE 4 A suspension of 0.0198 g of 4-benzylidene-7-N- phenylacety-amino-8-oxo-5-thial -azabicylo[ 4,2,o]oct-2-ene-2-carboxylic acid in 1.5 ml of methanol, cooled in ice water, is treated with an excess of a 2 percent strength solution of diazomethane in ether, added in portions; the evolution of nitrogen starts immediately and the solid material dissolves. The addition of diazomethane is stopped as soon as the yellow discoloration persists for 2-3 minutes. The volatile constituents are removed in a rotational evaporator and the residue is crystallized by adding a few drops of methanol.
  • EXAMPLE 6 A mixture of 0.128 g of isomer A of a-(Z-carbo-tertbutyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo-[ 3 ,2,0]heptyl )-a-[ 4-nitro-phenylacetyl methylene1-acetic acid tert.-butyl ester in 1 ml of trifiuoroacetic acid is allowed to stand for 44 hours at 20C.
  • the orange'colored reaction mixture containing the 7-amino-4-(4-nitrobenzylidene)-8-oxo-5-thia-1 azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7-amino-c'ephalosporanic acid) or 7- amino-2-(4-nitro-benzylidene)-A -cephem-4-carboxylic acid, is then diluted with 5 ml of dry dioxane and mixed with a solution of 0.155 g of phenylacetyl chloride in 2 ml of dioxane.
  • EXAMPLE 7 A solution of 0.023 g of crude 4-(4-nitro-benzylidene )-7-N-phenylacetyl-amino-8-oxo-5 thia- 1 azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid), obtained from crystallization mother liquor (Example 6), in 1 ml of methanol is treated with an excess of diazomethane in ether and allowed to stand for a few minutes at room temperature, and is then evaporated in a rotatory evaporator.
  • the residue is purified by means of thin layer chro matography (silica gel plate; 20 l0X0.l5 cm), the chromatogram being developped with a 2:1-mixture of hexane and ethyl acetate and with ethyl acetate alone.
  • the orange-colored band is extracted with ethyl acetate and the 4-(4-nitrobenzylidene)-7-N-phenylacetyl-arnino-S-oxo-S-thia-l-aza-bicyclo-[4,2,0]oct- 2-ene-2-carboxylic acid methyl ester (configuration of 7-aminocephalosporanic acid) or 2-(4-nitro-benzy 23 lidene )-7-N-phenylacetylamino-A -cephem-l-carboxylic acid methyl ester of the formula GOOCH;
  • EXAMPLE 8 A solution of 0.12 g of the isomer A of a-(2-carbotert.-butyloxy-3,3-dirnethyl-7'oxo-4-tl'iia-2,6-diaza-6- bicyclo 3 ,2 ,0]heptyl )-a-[ (4-methoxy-phenylacetyl methylene]-acetic acid tert.-butyl ester in 1 ml of precooled trifluoro-acetic acid is allowed to stand for 2 hours at -20C.
  • reaction mixture containing the 7-amino-4-( 4-methoxybenzyli-dene )-8-oxo-5-thia- 1- azabicyclo[4,2,0oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (4-methoxybenzyliden-A -cephem-4-carboxylic acid, is mixed with ml of dioxane and treated with a solution of 0.154 g of phenylacetyl chloride in 2 ml of dry dioxane. After 3 hours at room temperature, 10 drops of water are added and the solution is allowed to stand for a further hour.
  • the 4-(4- methoxy-benzylidene)-7-N-phenylacetyl-amino-8-oxo- S-thial -aza-bicyclo[4,2,0 ]oct-2-ene-2-carboxylic acid (configuration of -7-amino'cephalosporanic acid) or 2- (4-m ethoxy-benzylidene )-7-N-phenylacetylamino-A cephem-4-carboxylic acid of the formula is eluted with a 2:1-mixture of benzene and acetone and melts as a yellow product at 201203C after crystallization from a mixture of acetone and benzene; ultra-violet absorption spectrum in ethanol: A 366 my.
  • EXAMPLE 9 A mixture of 0.0052 g of 4-( 4-methoxybenzylidene 7-N-phenylacetyl-amino-8-oxo-5-thial -a2abicyclo[4,2,0l'oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) in 2 ml of methanol is mixed with 2 ml of a 2 percent solution of diazomethane in ether. The mixture is allowed to stand for 3 minutes at room temperature, the volatile constituents are then evaporated off and the residue is crystallized from a mixture of methanol and ether.
  • EXAMPLE 10 A solution of 0.232 g of the isomer A of a-( 2-carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo[3,2,0]heptyl)-a-[(4-chlorophenylacetyl)- methylene]-acetic acid tert.-butyl ester in 2 ml of trifluoroacetic acid is allowed to stand for 21 hours at -20C.
  • the solution is mixed with 15 ml of dry dioxane and 0.25 g of freshly distilled phenyl-acetyl chloride are added to the mixture, which contains the 7-amino-4-(4- chlorobenzylidene )-8-oxo-5 -thial-azabicyclo- [4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7- amino-cephalosporanic acid) or 7-amino-2-(4- chlorobenzylidene)-A -cephem-4-carboxylic acid.
  • the reaction solution is kept for 3 hours at room temperature and is then mixed with 0.3 ml of water and left to stand for 1 hour at room temperature.
  • EXAMPLE 11 A solution of 0.3285 g of the isomer A (trans) of a- (2-carbo-tert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo 3 ,2,0 ]heptyl)-a-( cyclohexylacetylmethylene)-acetic acid tert.-butyl ester in 2.3 ml of precooled trifluoroacetic acid is left to stand for 16% hours at 20C.
  • reaction mixture containing the 7 am ino-4-cyclohexyl-methylene-8-oxo-5-thia- 1 azabicyclo[4,2,0]oct-2-ene-2-car-boxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- cyclohexylmethylene-A -cephem-4-carboxylic acid, is mixed with 0.13 g of phenylacetyl chloride in 14 ml of dioxane and the mixture is kept at room temperature for 3 hours.
  • EXAMPLE 12 A mixture of 0.4 g of a-(2-carbo-tert.-butyloxy3,3- dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)a-(phenylacetylmethylene)-acetic acid tert.-butyl ester in 4 ml of trifluoroacetic acid is left to stand for 20 hours at 20C; the trifluoroacetic acid is removed under reduced pressure (oil pump) and the orangecolored residue, containing the 7-amino-4-benzylidene-S-oxo-S-thia-lazabicyclo[4,2,0]oct-2-ene-2- carboxylic acid (configuration of 7-aminocephalosporanic acid) or 7-amino-2-benzyliden-N- cephem-4-carboxylic acid, is mixed with 4 ml of a solution, cooled to 15C, of the mixed an
  • a suspension is thus obtained, which is adjusted to a volume of 14 ml with methylene chloride at -15C and used in this form).
  • the reaction mixture is treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride, stirred for 2 hours at room temperature and then diluted with 30 ml of ethyl acetate.
  • the mixture is washed with a concentrated sodium chloride solution in water, containing hydrochloric acid (15 ml of the sodium chloride solution contain 1.5 ml of 1N hydrochloric acid) and with a concentrated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure.
  • the residue from the mother liquor is chromatographed on 20 g of acid-washed silica gel, with neutral constituents, cyanoacetic acid and trichloroacetic acid being eluted with a :5-mixture of benzene and acetone and a further quantity of the desired product being eluted with a 2:1-mixture of benzene and acetone; this product melts at 225227C (decomposition) after crystallization from ethyl acetate and ether; ultra-violet absorption spectrum: A 353 my. and 240-265 mp. (broad shoulder) (in ethanol), A 346 my.
  • EXAMPLE 13 A solution of 0.023 g of 4-benzylidene-7-N-cyanoacetylamino-8-oxo5-thial azabicyclo [4 ,2 ,0 loot-2- ene-Z-carboxylic acid (configuration of 7-aminocephalosporanic acid) in about 2 ml of methanol is treated with a large excess of a 2 percent solution of diazomethane in ether. After standing for 2 minutes at room temperature, the excess of the diazomethane and the solvents are evaporated and the crystalline residue is purified by means of preparative thin layer chromatography on a silica gel plate, using a 95:5-mixture of chloroform and methanol.
  • EXAMPLE 14 A mixture of 0.328 g of a-(2-carbo-tert.-butyl-oxy- 3,3dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0 ]heptyl)-a-(4-nitrophenylacetyl-methylene)-acetic acid tert.-butyl ester and 3 ml of trifluoroacetic acid is left to stand at 20C for 44 hours.
  • the trifluoroacetic acid is removed under reduced pressure (oil pump) and the residue, containing the 7-amino-4-(4-nitrobenzylidene)-8-oxo-5-thia-1-azabicyclo[4,2,0]2-ene-2- carboxylic acid (configuration of 7-aminocephalosporanic acid) or 7-amino-2-(4-nitrobenzylidene)-A -cephem-4-carboxylic acid,is treated with 3 ml of a solution of a mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (for manufacture, see Example 12), followed by 1.5 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.
  • the reaction mixture is kept at room temperature for 2 hours and is then diluted with 15 ml of ethyl acetate and washed with concentrated aqueous sodium chloride containing hydrochloric acid ml of the sodium chloride solution contain 1 ml of 1N hydrochloric acid) and with a concentrated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on 10 g of acid-washed silica gel.
  • the excess cyanoacetic acidand trichloroacetic acid and an orange-colored neutral constituent are eluted with a 100:5-mixture of benzene and acetone, and the amorphous yellowishorange 7-N-cyanoacetyl-amino-4-(4-nitrobenzylidene )-8-oxo-5 thial -azabicyclo[4,2,0 2-ene-2- carboxylic acid (configuration of 7-aminocephalosporanic acid) or 7-N-cyanoacetyl-amino-2-(4- nitro-benzylidene )-A -cephem-4-carboxylic acid of the formula is eluted with a 2:1-mixture of benzene and acetone; ultra-violet absorption spectrum: A 388 mp.
  • EXAMPLE 15 A solution of 0.058 g of the isomer A of a-( 2-carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo[3,2,0]heptyl)-a-(phenylacetylmethylene)- acetic acid tert.-butyl ester in 1.5 ml of acetic acid, containing 0.015 g of p-toluenesulphonic acid, is left to stand for 18 hours at room temperature and then diluted with 12 ml of dioxane.
  • the resulting solution is mixed with 0.08 g of phenylacetyl chloride and after 3 hours with 0.5 ml of water.
  • the reaction mixture is left to stand for 1 hour at room temperature, the volatile constituents are then evaporated under a high vacuum and at room temperature, and the residue is chromatographed on 10 g of acid-washed silica gel.
  • EXAMPLE 16 A mixture of 0.35 g of the isomer A of a-( 2-carbotert.-butyloxy-3,3dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo[3,2,0]heptyl)-a-(isobutyrylmethylene)-acetic acid tert.-butyl ester and 2.8 ml of trifluoroacetic acid is allowed to stand at 20C for 24 hours; the trifluoroacetic acid is then distilled off under a high vacuum at room temperature.
  • the residue which contains 7-amino-4-isopropylidene-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- isopropylidene-A -cephem-4-carboxylic acid, is treated with 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (for preparation, see Example 12), and then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.
  • the resulting solution is allowed to stand at room temperature for 2 hours and is then diluted with 40 ml of ethyl acetate.
  • the organic solution is washed with ml of water, 2 ml of 2N- hydrochloric acid and twice with a saturated aqueous sodium chloride solution.
  • the aqueous phases are extracted with a small quantity of ethyl acetate, and the combined organic solutions are dried over sodium sulfate, then evaporated.
  • Example 12 then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.
  • the solution is allowed to stand at room temperature for 2 hours, then diluted with 40 ml of ethyl acetate, and washed with 15 ml of water, with 2 ml of 2N- hydrochloric acid, and twice with a concentrated aqueous sodium chloride solution; the aqueous solutions are 2.87-4.30fl/L,
  • the residue from the mother liquor is chromatographed on 10 g of acid-washed silica gel.
  • the column is pre-washed with a :5-mixture of benzene and ethyl acetate, and with a 2zl-mixture of benzene and ethyl acetate, another quantity of 4-(4-chlorobenzylidene)-7 -N-cyanoacetyl-amino-8-oxo-5 thialazabicyclo[4 ,2 ,0 ]oct-2-ene2-carboxylic acid is eluted which is purified by crystallization from a mixture of ethyl acetate and ether.
  • EXAMPLE 18 A mixture of 0.367 g of the isomer A of a-(2-carbotert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6diaza-6- bicyclo 3 ,2,0 heptyl )-a- 3-phenylpropionyl methylene1-acetic acid tert.-butyl ester in 3 ml of trifluoroacetic acid is allowed to stand at 20C for 22 hours, after which the trifluoroacetic acid is distilled off at room temperature under a high vacuum.
  • Example 12 then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.
  • the batch is allowed to stand at room temperature for 2 hours, then diluted with 40 ml of ethyl acetate, and the mixture is washed with 15 ml of water, with 2 ml of 2N hydrochloric acid, and twice with a saturated aqueous sodium chloride solution; the aqueous solutions are each extracted with ethyl acetate.
  • the combined organic solutions are dried over sodium sulfate and evaporated.
  • the residue from the mother liquor is chromatographed on 10 g of acid-washed silica-gel. With a 2:1- mixture of benzene and acetone, cyanoacetic acid and trichloroacetic acid are washed out, and then a further quantity of 7-N cyano-acetyl-amino-4-( 2-phenyll l ethylidene )-8-oxo-5-thial -azabicyclo[4,2,0 ]oct-2ene- 2-carboxylic acid is eluted with a 2:1-mixture of benzene and acetone. The product is purified by trituration with benzene.
  • the syrupy triethylamine salt is soluble in chloroform and water; ultra-violet absorption spectrum; in ethanolk 307 my, and in ethanol/hydrogen chloride A 317 mu; infrared absorption spectrum (in chloroform): characteristic bands at 2.90-4.30 5.60-5.65u, 5.7511. (shoulder), 59511., 6.02p. (shoulder) and 6.16-6.30 (broad).
  • EXAMPLE 20 A mixture of 0.2 g of the isomer A (trans) of a-(2- carbo-tert.-butyloxy-3 ,3-dimethyl-7-0xo-4-thia-2,6- diaza-6-bicyclo[3,2,0]heptyl)-a-(phenylacetylmethylene )-acetic acid acid tert.-butylester in 1.5 ml of trifluoroacetic acid is allowed to stand for 19 hours at 20C. The trifluoroacetic acid is evaporated at room temperature, finally under high vacuum.
  • a solution of 0.052 ml of isobutyl chloroformate in 0.5 ml tetrahydrofuran is treated at 10C with 0.101 g of D-N-carbo-tert.butyloxy-phenylglycine and 0.055 ml of t'riethylamine in 2 ml of tetrahydrofuran and after 10 minutes, the previously mentioned solution of cyclization product is added. The resulting mixture is allowed to stand for 1 hour at 10C and for another hour at room temperature. The volatile components are then distilled off under reduced pressure, the residue is dissolved in 25 ml of ethyl acetate and extracted three times with water.
  • the combined aqueous extracts are acidified with 2N hydrochloric acid to pH 3 and extracted with ethyl acetate.
  • the organic solution is dried over sodium sulfate and evaporated under reduced pressure.
  • the residue is chromatographed on 3 g of acid-washed silicagel, a mixture of benzene and ethyl acetate with a gradual increase of ethyl acetate from 2 percent to 50 percent being used as mobile phase.
  • a further amount of this product can be isolated from the residue of the first ethyl acetate solution; it contains a small amount of the 4-benzylidene-7-N-(N- carbo-tert.-butyloxy-D-phenylglycyl)-amino-8-oxo-5- thia-l-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid tert.-butyl ester (configuration of 7-aminocephalosporanic acid) or 2-benzylidene-7-N-(N-carbo tert.butyloxy-D-phenylglycyl)-amino-A -cephem-4- carboxylic acid tert.-butylester.
  • EXAMPLE 21 A solution of 0.255 g of the isomer A (trans) of a-( 2- carbo-tert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo[ 3 ,2,0 ]heptyl)-a-[ 4-chlorobutyryl methylene]-acetic acid tert.-butyl ester in 5 ml of precooled trifluoroacetic acid is allowed to stand at -C for 20 hours.
  • a total of 4 ml of trifluoroacetic acid is distilled off and 15 ml of dioxane and 0.25 g of phenylacetyl chloride is added to the solution containing the 7-amino-4-( -chloro-1 l -propylidene )-8-oxo-5-thial azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- 3-chloro- 1 l -propylidene )-A"-cephem-4-carboxylic acid.
  • infrared absorption spectrum in methylene chloride: characteristic bands at 2.97p., 3.30-3.50 5.6lp., 5.8 lp., 5.94m 6.23;! and 6.74u.
  • the starting materials used in the above Examples can, for example, be prepared as follows:
  • EXAMPLE 22 A mixture of 5 g of 2-carbo-tert.-butyloxy-3,3- dimethyl-4-thia-2,6-diaza-bicyclo[3,2,0]heptan-7-one and 5.5 g of glyoxylic acid tert.-butyl ester hydrate in 40 ml of dioxane is stirred for 13%hours at C in a closed vessel and then evaporated. The residue is dissolved in 1000 ml of pentane, washed three times with 500 ml of water and once with 200 ml of a saturated aqueous sodium chloride solution, dried over dry sodium sulphate and evaporated.
  • EXAMPLE 23 A mixture of 6 g of a lzl-mixture of the isomers of a- (2-carbo-tert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo[ 3 ,2,0 ]heptyl)-a-hydroxy-acetic acid tert.-butyl ester and 10.5 g of the so-called polystyrene l-lunig base (manufactured by warming a mixture of 100 g of chloromethyl-polystyrene [J.Am.Chem.Soc.
  • EXAMPLE 24 A solution of 1 1.3 g of a crude mixture of the isomers of a-( 2-carbo-tert.-butyloxy-3,3-dimethyl-7-oxo-4- thia-2,6--diaza-6-bicyclo[3,2,0]heptyl)-a-chloroacetic acid tert.-butyl ester in 150 ml of absolute dioxane is mixed with 11.4 g of triphenylphosphine and 10.8 of polystyrene l-lunig base" (or diisopropylaminomethylpolystyrene), stirred for 17 hours at 55C under a nitrogen atmosphere, then cooled and filtered through a glass filter.
  • Triphenylphosphine and a small amount of triphenylphosphine-sulphide are eluted with 2,000 ml of a 3: l-mixture of hexane and ethyl acetate, and the a- (2-carbo-tert.-butyloxy-3 ,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo[3,2,0]heptyl)-a-(triphenylphosphoranylidene)-acetic acid tert.-butyl ester of the formula is eluted with a further 4,000 ml of the 3:1-mixture of hexane and ethyl acetate; an additional quantity of the impure product can be obtained with 1,500 ml of the same solvent mixture.
  • a further quantity of the product can be isolated from the mother liquor by crystallization in an ether-pentane mxiture.
  • EXAMPLE 25 A solution of 2 g of a-(2-carbo-tert.-butyl-oxy-3,3- dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo 3 ,2 ,0 heptyl)-a-(triphenyl-phosphoranylidene)acetic acid tert.- butyl ester and 0.7 g of benzylglyoxal (in the enol form) in 30 ml of dry toluene is heated for 23 hours at C (bath tempera-ture) in a nitrogen atmosphere, and is then mixed with a further quantity of 0.2 g of benzylglyoxal; the reaction mixture is heated for 22 hours at 80C.
  • C bath tempera-ture
  • the above isomer mixture is again chromatographed on 60 g of acid-washed silica gel, elution being carried out with a 99: l-mixture of benzene and ethyl acetate.
  • a product consisting mainly of benzylglyoxal ' is obtained in the first run, and then a fraction I, consisting mainly of the isomer A, is obtained with ml, a fraction 11, consisting of a mixture of both isomers with 250 ml, and a fraction III, consisting mainly of isomer B with 300 ml.
  • the above three fractions are recrystallized from hexane, whereupon fraction I yields the isomer A (trans); m.p.
  • EXAMPLE 26 A solution of 0.0162 of isomer B of a-(Z-carbo-tert. butyloxy-3,3-dimethyl-7-oxo-4-thia 2,6-diaza -6- bicyclo-[3,2,0]heptyl)-a-(phenylacetylmethylene)- acetic acid tert.-butyl ester in 10.6 ml of benzene is irradiated with ultra-violet light at room temperature in a Pyrex glass vessel under a nitrogen atmosphere.
  • the non-crystalline residue consists of an approximately 42:58-mixture of isomer A and isomer B of a-(2-carbo-tert.-butyl-oxy-3,3- dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-a-(phenylacetylmethylene)-acetic acid tert.-butyl ester.
  • the crystalline isomer B and fractions which predominantly consist of isomer B of a-(2-carbo-tert.- butyl-oxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6- bicyclo[3,2,0]heptyl)-a-(phenylacetylmethylene)- acetic acid tert.-butyl ester can in the same manner be isomerized to give isomer mixtures containing isomer A and isomer dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl) -a-(phenylacetylmethylene)-acetic acid tert.-butyl ester.
  • EXAMPLE 27 One g of a-(2-carbo-tert.-butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl)-a- (triphenylphosphoranylidene)-acetic acid tert.-butyl ester is treated under nitrogen with 0.65 g of isopropylglyoxal in 7 ml of toluene, and the mixture is allowed to stand for 8 days at 90C.
  • the solvent and the excess isopropylglyoxal (in the enol form) are removed under reduced pressure at 50C and the residue is chromatographed on 50 g of acid-washed silica gel; elution is carried out with a 4: l-mixture of hexane and ethyl acetate.
  • the first 150ml elute the isomer A (trans) of a-( 2- carbo-tert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo-[3,2,0]heptyl)-a-(isobutyrylmethylene)-acetic acid tert.-butyl ester of the formula co o 0111);
  • the isomer B (cis) of a-(2-carbo-tert.-butyloxy-3,3- dimethyl-7-oxo -4-thia-2,6-diaza-6-bicyclo[ 3 ,2,0]heptyl)-a-(isobutyrylmethylene)-acetic acid tert.-butyl ester is obtained on further elution with the same solvent mixture and melts at 146l47C after crystallization from a mixture of hexane and ethyl acetate; ultraviolet absorption spectrum: in ethanol A "m 289 my; in potassium hydroxide/ethanolA 328 mu; and in hydrogen chloride/ethanolA MI 328 mp; infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60-5.66 [.L, 5.75 p.(shoulder), 5.85-5.95 and 6.3 1 .1..
  • EXAMPLE 28 A mixture of 0.05 g of a-(Z-carbo-tert.-butyloxy-3,3- dimethyl-7-oxo4-thia-2,6-diaza-6-bicyclo[3,2,0]heptyl) -a-(triphenylphosphoranylidene )-acetic acid tertbutyl ester and 0.0355 g of 4-nitrobenzyl-glyoxal in 0.6 ml of toluene is heated at C for 7 hours.
  • the solvent is then distilled off under reduced pressure and the residue is chromatographed on a thin layer silica gel plate (20X20X0.l5 cm), the chromatogram being developped with a 2zl-mixture of hexane and acetic acid ethyl ester.
  • the isomer B crystallizes from hexane, m.p. 173C; Rf-valve 0.29; ultra-violet absorption spectrum in ethanol: A 293 mu, and in potassium hydroxide/ethanol:A 335 my. and 285

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US00881639A 1968-12-11 1969-12-02 4-substituted methylene-7-amino-8-oxo-5-thia-1-aza-bicyclo(4,2,0 oct-2-ene-2-carboxylic acids Expired - Lifetime US3719672A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1849968A CH537415A (de) 1968-12-11 1968-12-11 Verfahren zur Herstellung von thiazabicyclischen Verbindungen
CH1037269 1969-07-08

Publications (1)

Publication Number Publication Date
US3719672A true US3719672A (en) 1973-03-06

Family

ID=25706565

Family Applications (1)

Application Number Title Priority Date Filing Date
US00881639A Expired - Lifetime US3719672A (en) 1968-12-11 1969-12-02 4-substituted methylene-7-amino-8-oxo-5-thia-1-aza-bicyclo(4,2,0 oct-2-ene-2-carboxylic acids

Country Status (8)

Country Link
US (1) US3719672A (cs)
AT (1) AT299220B (cs)
BE (1) BE742934A (cs)
BR (1) BR6914981D0 (cs)
DE (1) DE1960917A1 (cs)
FR (1) FR2025863B1 (cs)
GB (2) GB1289850A (cs)
NL (1) NL6918536A (cs)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4073903A (en) * 1975-10-01 1978-02-14 Pierrel S.P.A. 3-Desacetoxymethyl-3- 5'(1-methyltetrazolyl)thio!methyl-7- 1-(4-nitroimidazolyl)acetyl!aminocephalosporanic acid
US4113940A (en) * 1973-03-15 1978-09-12 Fujisawa Pharmaceutical Co., Ltd. 7-amino 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives and processes for preparation thereof
US4147863A (en) * 1974-09-04 1979-04-03 Sankyo Company Limited 7-D-(-)-mandelamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid
US4152433A (en) * 1976-03-12 1979-05-01 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutical compositions
US4203897A (en) * 1972-10-20 1980-05-20 Fujisawa Pharmaceutical Company, Limited Penam derivatives
US4218374A (en) * 1972-10-20 1980-08-19 Fujisawa Pharmaceutical Company, Limited Penam derivatives
US4225707A (en) * 1976-06-28 1980-09-30 Fujisawa Pharmaceutical Company, Limited 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds
US4305937A (en) * 1978-08-17 1981-12-15 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and antibacterial pharmaceutical compositions containing them
US4385176A (en) * 1973-03-15 1983-05-24 Fujisawa Pharmaceutical Co., Ltd. Process for preparation of 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4203897A (en) * 1972-10-20 1980-05-20 Fujisawa Pharmaceutical Company, Limited Penam derivatives
US4218374A (en) * 1972-10-20 1980-08-19 Fujisawa Pharmaceutical Company, Limited Penam derivatives
US4113940A (en) * 1973-03-15 1978-09-12 Fujisawa Pharmaceutical Co., Ltd. 7-amino 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives and processes for preparation thereof
US4385176A (en) * 1973-03-15 1983-05-24 Fujisawa Pharmaceutical Co., Ltd. Process for preparation of 2-lower alkyl-2 or 3-cephem-4-carboxylic acid derivatives
US4147863A (en) * 1974-09-04 1979-04-03 Sankyo Company Limited 7-D-(-)-mandelamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylic acid
US4073903A (en) * 1975-10-01 1978-02-14 Pierrel S.P.A. 3-Desacetoxymethyl-3- 5'(1-methyltetrazolyl)thio!methyl-7- 1-(4-nitroimidazolyl)acetyl!aminocephalosporanic acid
US4152433A (en) * 1976-03-12 1979-05-01 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and pharmaceutical compositions
US4225707A (en) * 1976-06-28 1980-09-30 Fujisawa Pharmaceutical Company, Limited 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds
US4305937A (en) * 1978-08-17 1981-12-15 Fujisawa Pharmaceutical Co., Ltd. 2-Lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid compounds and antibacterial pharmaceutical compositions containing them

Also Published As

Publication number Publication date
BR6914981D0 (pt) 1973-05-24
NL6918536A (cs) 1970-06-15
FR2025863B1 (cs) 1973-04-06
BE742934A (cs) 1970-06-10
AT299220B (de) 1972-06-12
DE1960917A1 (de) 1970-07-09
GB1292729A (en) 1972-10-11
GB1289850A (cs) 1972-09-20
FR2025863A1 (cs) 1970-09-11

Similar Documents

Publication Publication Date Title
US4267320A (en) Cephalosporin antibiotics
US3708479A (en) Acyloxymethyl esters of alpha-ureidocyclo-hexadie nylalkylene-cephalosporins
JPH0369353B2 (cs)
US3719672A (en) 4-substituted methylene-7-amino-8-oxo-5-thia-1-aza-bicyclo(4,2,0 oct-2-ene-2-carboxylic acids
US4735937A (en) 8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-ene compounds
JPS6124399B2 (cs)
US3799938A (en) Certain 4-thia-2,6-diazabicyclo(3.2.0)heptane derivatives
JPS5934714B2 (ja) ７β−アミノ−セフアム−３−オル−４−カルボン酸化合物または相当する３−θ−エステルの製法
US3481948A (en) 2,2 - disubstituted - 3 - acyl - 5alpha - azidothiazolidine-4-carboxylic acids and derivatives
US3842072A (en) Certain 2alpha-(2-hydroxymethyl-2-propylmercapto)-3-amino-azetidin-4-one compounds
US3705892A (en) Rearrangement of penicillin
JPS6124398B2 (cs)
FI75165C (fi) Foerbaettrat foerfarande foer framstaellning av penicillansyraklormetylestrar.
US3880833A (en) Certain bis-(3-amino-2-oxo-1-azetidinyl)-disulfides
JPS5938955B2 (ja) Ｏ−置換された７β−アミノ−３−セフエム−３−オ−ル−４−カルボン酸化合物の製法
US3832347A (en) Imino-halides of 3-amido-2-halo-1-(1'-protected carboxy-2'-methyl-1'-propenyl)-4-azetidinones
US4052408A (en) Oxyacetic acid compounds and process for their manufacture
CA1093549A (en) Cephalosporin antibiotics
US3971780A (en) Thio-β-lactam cephalosporins
US3679676A (en) Thiadiazabicycloalkane compound
US3703512A (en) Isopropenylmercapto-3-alpha-acylamino-azetidin-4-ones
US3809700A (en) Certain 5,6-dioxopyrrolo(2,1-b)thiazoles
US3801567A (en) Process for the manufacture of 6-amino-3-carbonylamino-penam compounds
US3705160A (en) Thiazacyclic hydroxy compounds and process for their manufacture
US3711464A (en) 1-formyl-2-alpha-(2-acyloxy-2-propylmercapto)-3 alpha-n-acyl-aminoazetidin-4-ones and process for their preparation